The effectiveness and clinical outcomes of low-dose ketamine on the inflammatory stress response in digestive laparotomy surgery: A case series

Tjokord Gade Agung Senapathi; I Putu Pramana Suarjaya; I Made Gede Widnyana; Made Septyana Parama Adi

doi:10.4103/BJOA.BJOA_18_19

CASE REPORT

Year : 2020 | Volume : 4 | Issue : 2 | Page : 62-65

The effectiveness and clinical outcomes of low-dose ketamine on the inflammatory stress response in digestive laparotomy surgery: A case series

Tjokord Gade Agung Senapathi, I Putu Pramana Suarjaya, I Made Gede Widnyana, Made Septyana Parama Adi
Department of Anesthesiology, Pain Management, and Intensive Care, Udayana University, Sanglah General Hospital, Bali, Indonesia

Date of Submission	12-Dec-2019
Date of Decision	17-Feb-2020
Date of Acceptance	28-Feb-2020
Date of Web Publication	11-May-2020

Correspondence Address:
Dr. Made Septyana Parama Adi
Jl SMA 3 No. 17 Denpasar, Bali 80235
Indonesia

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/BJOA.BJOA_18_19

Abstract

Surgery and anesthesia may cause inflammatory response. Ketamine, through its various anti-inflammatory activities, is expected to control this inflammatory response. Six patients who underwent digestive laparotomy surgery were randomly assigned to receive ketamine 0.3 mg/kgBW or intravenous NaCl 0.9%. Patients' blood was collected twice; pain score and total morphine consumption were also recorded. Pain score was assessed using the visual analog score and total morphine requirement was measured using patient-controlled analgesia. In this case series, we found that inflammation markers such as neutrophils count and C-reactive protein in the ketamine group were lower than the normal saline group. We also found that pain score and total morphine requirements were lower in the ketamine group compared to the normal saline group. In conclusion, the administration of a low dose of ketamine at the end of surgery showed decrease in inflammation markers, pain scores, and the need for postoperative opioid.

Keywords: C-reactive protein, neutrophils count, total morphine consumption, visual analog score

How to cite this article:
Agung Senapathi TG, Pramana Suarjaya I P, Gede Widnyana I M, Parama Adi MS. The effectiveness and clinical outcomes of low-dose ketamine on the inflammatory stress response in digestive laparotomy surgery: A case series. Bali J Anaesthesiol 2020;4:62-5

How to cite this URL:
Agung Senapathi TG, Pramana Suarjaya I P, Gede Widnyana I M, Parama Adi MS. The effectiveness and clinical outcomes of low-dose ketamine on the inflammatory stress response in digestive laparotomy surgery: A case series. Bali J Anaesthesiol [serial online] 2020 [cited 2023 Mar 23];4:62-5. Available from: https://www.bjoaonline.com/text.asp?2020/4/2/62/284187

Introduction

Surgery and anesthesia may cause condition that can trigger patients' stress response.^[1] Systemic inflammatory response to surgery has been studied in many surgical settings.^[2] Neutrophils and C-reactive protein (CRP) are known to increase dramatically in response to injury, infection, and inflammation.^[3],[4]

Ketamine as an anesthetic agent can avoid the exacerbation of pro-inflammatory reactions without affecting the production of anti-inflammatory cytokines.^[5] Low-dose ketamine can significantly reduce the level of serum interleukin (IL-6), CRP, neutrophil, and IL-10 in patients who underwent heart surgery.^[6] The use of ketamine in upper abdominal and thoracic procedures also reduced the need of postoperative opioid.^[7]

Case Report

Six patient aged ranged between 18 and 64 years old, with the American Society of Anesthesiology physical status I-II who underwent laparotomy with general anesthesia were enrolled in this case series. These patients were randomly divided into two groups (n = 3): patients who received ketamine 0.3 mg/kg BW (KET group) and NaCl 0.9% (NS group).

All of the patients received premedication with intravenous midazolam 0.05 mg/kg BW. The patients were monitored using standard monitoring. Baseline vital signs were also recorded. Anesthesia was induced using propofol 2 mg/kg BW and fentanyl 2 mcg/kg BW. Atracurium 0.5 mg/kg BW was also administered to facilitate tracheal intubation. Anesthesia was then maintained using compressed air, O2, sevoflurane, fentanyl, and intermittent atracurium. The first blood sample was taken after intubation. The second blood sample was taken 24 h postoperative. After wound closure, the KET group received ketamine 0.3 mg/kg (made up to 3 ml with normal saline) and NS group received NaCl 0.9% 3 ml. At the end of the surgery, anesthesia was discontinued, and the patients were monitored in the postanesthesia care unit for 1 h. Patients received ketorolac 30 mg every 8 h and were also on patient-controlled analgesia (PCA) using morphine with concentration 1 mg/ml and demand dose 1 mg with a lock of interval 6 min and maximal dose 10 mg every 4 h. Total morphine consumption was measured 24 h postoperative.

Discussion

Surgery and general anesthesia are known to cause a decrease in body immunity through disorders in the immune system itself or suppression of the immune system due to excessive performance of the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system.^[8] Disruption in the regulation of inflammatory response can increase the body's vulnerability to infection, as well as various other postoperative complications.^[1] The balance between proinflammatory and anti-inflammatory cytokines is a vital factor in the acute phase of the immune and inflammatory response due to surgical stress stimulation.^[5] Elective abdominal surgery triggers an acute inflammatory response characterized by the rapid increase in circulating IL-6 concentration, which is still increasing significantly at least up to the 3^rd postoperative day.^[2]

Recent studies mainly examine the relationship of CRP with the body's inflammatory processes. CRP is synthesized by the liver and induced the release of IL-6 by macrophage cells. Blood CRP levels can increase by at least 25% in acute inflammation and will decrease within 18–20 h after the trigger factors subside.^[4]

In this case series, the inflammatory stress response was assessed from increased CRP in both groups [Table 1] and [Table 2]. The KET Group had lower level of CRP compared to the NS group [Figure 1]. Ketamine is known to inhibits the production of CRP by decreasing the activation of nuclear factor kappa B in liver cells.^[4],[6] Ketamine may also reduce the inflammatory process by inhibiting the performance of the cyclooxygenase-2 (COX-2) enzyme produced by the liver. This COX-2 enzyme plays an important role in the inflammatory process through prostaglandin cascade.^[9] Low-dose ketamine (0.25–0.5 mg/kg BW) significantly suppressed the intraoperative and postoperative increase of serum IL-6 and CRP in patients undergoing coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass and significantly decreased superoxide production.^[10]

Table 1: Characteristics of c-reactive protein, neutrophil, Visual Analog Score, total morphine consumption in the ketamine group

Click here to view

Table 2: Characteristics of c-reactive protein, neutrophil, Visual Analog Score, total morphine consumption in the normal saline group

Click here to view

Figure 1: Level of C-reactive protein serum postinduction and 24 h postoperative. Blue column: C-reactive protein postinduction in KET group, Orange column: C-reactive protein 24 h postoperative in KET group, Green column: C-reactive protein postinduction in NS group, Gray column: C-reactive protein 24 h postoperative in NS group

Click here to view

Neutrophils are known as “front-line” defenders. In humans, 50%–70% of circulating leukocytes are neutrophils, it controlled by granulocyte-colony stimulating factor (G-CSF). Under inflammatory conditions, the estimated time that neutrophils spend in the circulation increases by ten-fold, from 5–10 h to 5 days.^[3]

In this case series, neutrophil increased in both groups [Table 1] and [Table 2]. However, in the KET group, the neutrophil increase was lower than the NS group [Figure 2]. These results are also similar to the study conducted by Zilberstein et al. 2002 which found that the addition of small-dose ketamine to general anesthesia attenuates increased production of the superoxide anion (O2-) by neutrophils for four until 6 days after CABG. In addition, ketamine attenuated the percentage of neutrophils on postoperative days 2–6.^[11] Ketamine decreases proinflammatory cytokines through the induction of apoptosis from these proinflammatory cytokine cells. Research by Braun et al. in 2010 found that ketamine induces apoptosis, both through the intrinsic and extrinsic pathways.^[12]

Figure 2: Neutrophil counts postinduction and 24 h postoperative. Blue column: Neutrophil postinduction in KET group, Orange column: Neutrophil 24 h postoperative in KET group, Green column: Neutrophil postinduction in NS group, Gray column: Neutrophil 24 h postoperative in NS group

Click here to view

The visual analog score of the KET group was found lower than the NS group [Figure 3]. The KET group also showed lower total morphine consumption compared to the NS group measured using PCA within 24 h [Figure 4]. Ketamine is known to produce antinociceptive through interactions with μ receptors on the spinal nerves, NMDA-receptor antagonists, and activation of the monoaminergic descending pain inhibitory pathway.^[13] For sedation and analgesia, ketamine is given at subanesthetic dose of 0.2–0.75 mg/kg BW intravenously. The effect of this analgesia is achieved at the plasma concentration of 100–150 ng/ml.^[14]

Figure 3: Visual analog score chart preoperative and 24 h postoperative. Blue column: Visual analog score preoperative in KET group, Orange column: Visual analog score 24 h postoperative in KET group, Green column: Visual analog score preoperative in NS group, Gray column: Visual analog score 24 h postoperative in NS group

Click here to view

Figure 4: Total morphine consumption 24 h. Blue column: Total morphine consumption in KET group, Green column: Total morphine consumption in NS group

Click here to view

In conclusion, the administration of a low-dose ketamine at the end of surgery showed a decrease in the inflammatory response, pain scores, and the need for postoperative opioids. Further study with more samples is needed to confirm this result.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Elenkov IJ, Chrousos GP. Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity. Ann N Y Acad Sci 2002;966:290-303.
2.	Bautmans I, Njemini R, De Backer J, De Waele E, Mets T. Surgery-induced inflammation in relation to age, muscle endurance, and self-perceived fatigue. J Gerontol A Biol Sci Med Sci 2010;65:266-73.
3.	Florence M. Neutrophils and inflammation: Unraveling a new connection. Biol Med (Aligarh) 2016;8:6.
4.	Cole DS, Watts A, Scott-Coombes D, Avades T. Clinical utility of peri-operative C-reactive protein testing in general surgery. Ann R Coll Surg Engl 2008;90:317-21.
5.	De Kock M, Loix S, Lavand'homme P. Ketamine and peripheral inflammation. CNS Neurosci Ther 2013;19:403-10.
6.	Roytblat L, Talmor D, Rachinsky M, Greemberg L, Pekar A, Appelbaum A, et al. Ketamine attenuates the interleukin-6 response after cardiopulmonary bypass. Anesth Analg 1998;87:266-71.
7.	Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth 2011;58:911-23.
8.	Homburger JA, Meiler SE. Anesthesia drugs, immunity, and long-term outcome. Curr Opin Anaesthesiol 2006;19:423-8.
9.	White PF, Ham J, Way WL, Trevor AJ. Pharmacology of ketamine isomers in surgical patients. Anesthesiology 1980;52:231-9.
10.	Cruz FF, Rocco PR, Pelosi P. Anti-inflammatory properties of anesthetic agents. Crit Care 2017;21:67.
11.	Zilberstein G, Levy R, Rachinsky M, Fisher A, Greemberg L, Shapira Y, et al. Ketamine attenuates neutrophil activation after cardiopulmonary bypass. Anesth Analg 2002;95:531-6.
12.	Braun S, Gaza N, Werdehausen R, Hermanns H, Bauer I, Durieux ME, et al. Ketamine induces apoptosis via the mitochondrial pathway in human lymphocytes and neuronal cells. Br J Anaesth 2010;105:347-54.
13.	Price DD, Mayer DJ, Mao J, Caruso FS. NMDA-receptor antagonists and opioid receptor interactions as related to analgesia and tolerance. J Pain Symptom Manage 2000;19:S7-11.
14.	Wiryana M, Sinardja IK, Budiarta IG, Senapathi TG, Widnyana M, Aryabiantara IW, et al. Low dose ketamine. BJOA 2017;1:13-9.